Exploration of the pathogenic mechanisms of inherited cardiomyopathies caused by cardiac troponin T mutations

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We created knock-in mice in which a deletion of three base-pairs coding for K210 in cardiac troponin T (cTnT) found in familial dilated cardiomyopathy (DCM) patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca^<2+> sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca^<2+> transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers of mutant mice was not significantly different from that of wild-type mice, suggesting that Ca^<2+> transient was augmented to compensate for decreased myofilament Ca^<2+> sensitivity. Nevertheless, mutant mice developed marked cardiac enlargement, heart failure and frequent sudden death recapitulating the phenotypes of DCM patients, indicating that global functional defect of the heart due to decreased myofilament Ca^<2+> sensitivity could not be fully compensated by just increasing the intracellular Ca^<2+> transient. We found that a positive inotropic agent, pimobendan, which directly increases myofilament Ca^<2+> sensitivity, had profound effects of preventing cardiac enlargement, heart failure and sudden death. These results verify the hypothesis that Ca^<2+> desensitization of cardiac myofilament is the absolute cause of the pathogenesis of DCM associated with this mutation and strongly suggest that Ca^<2+> sensitizers are beneficial for the treatment of DCM patients affected by sarcomeric regulatory protein mutations.